5, 10-methylene-19-nor-pregnanes and their preparation



United States Patent 3,296,270 5,10-METHYLENE-19-NOR-PREGNANES AND THEIR PREPARATION Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed Nov. 13, 1964, Ser. No. 411,130 16 Claims. (Cl. 260-397.3)

i i; Bit

In the above formulas, R and R represent lower alkyl, alkenyl or alkinyl radicals which may be the same or dilferent, such as methyl, ethyl, propyl, vinyl, propenyl, ethinyl, propinyl, etc.; R represents hydrogen, hydroxy or an acyloxy group of less than 12 carbon atoms; R represents hydrogen, a-methyl or fl-methyl; R represents a lower alkyl group and R represents hydrogen or a lower alkyl radical. V

The acyloxy groups above referred to are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, pro pionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and fi-chloropropionate.

These compounds are powerful progestational agents, useful in the treatment of menstrual disorders such as amenorrhea, dysmenorrhea, etc. and for maintenance of pregnancy and fertility control.

In addition they have anti-androgenic, anti-estrogenic and anti-gonadotrophic properties and lower the blood cholesterol level. v

"ice

The method for producing the compounds of the present invention is illustrated by the following sequence of reactions:

CH3 CH3 1/ M MR NWR3 go too O I l I R1 II CH3 CH3 d=0 (i=0 I...

MNR3 NWRS m too I i I, j

on, (1:0 n.

MR IQ we on 7 CH3 t U i W e we In the above formulas R, R R and R have the same meaning as heretofore set forth and R represents hydrogen or an acyloxy radical, preferably acetoxy.

In practicing the process illustrated above, there is employed as the starting compound a let-alkyl, alkenyl or alkinyl-20-ethylenedioxy-S,l0 methylene 19 norpregnan-3-one compound (I) which is obtained by treatment of A pregnene 3 3,l9-diol-20-one or the corre-'.

sponding 16-methyl or l7a-acetoxy compounds with ethylene glycol in benzene solution and in the presence of p-toluenesulfonic acid, to produce the corresponding 20-ethylenedioxy derivatives, oxidation at C-3 under mild Oppenauer condition to A -3-keto derivatives, re-

action of these compounds with 2-chloro-1,1,2-trifluorotriethylamine in acetonitrile to produce a mixture of 20-ethylenedioxy-5,10-methylene 19 nor A -pregnen- 3-one compounds and 20 ethylenedioxy-S,10-seco-5,19- cyclo 10,6 fluoro A pregnenes, and finally treatment of the 20 ethylenedioxy 5,10 rnethylene-19-nor-A pregnen-S-one compounds with a Grignard reagent, to produce a mixture of the la substituted 20 ethylenedioxy 5,10-methylene 19 nor pregnan-3-one and the 3 substituted 5,10 seco 5,19-cyclo-A -pregnatriene compounds, which is separated by chromatography, as described in my copending patent application Serial No. 346,074 filed February 20, 1964. The lot-alkyl, alkenyl or alkinyl 20 ethylenedioxy 5,10-methylene- 19-nor-pregnen-3-one (I) is treated with a lower alkyl, alkenyl or alkinyl magnesium halide such as methyl magnesium bromide,- ethyl magnesium bromide, vinylmagnesium bromide, ethinylmagnesium bromide, propargylmagnesium bromide, etc., in an inert organic solvent such as ether, benzene, tetrahydrofuran and the like, at a temperature comprised between room temperature and reflux, for a period of time of between 1 to 6 hours, to produce the corresponding 3-alkyl, alkenyl or alkinyl- 3-hydroxy-20-ethylenedioxy 5,10 methylene 19 norpregnane compounds (II), which are then dehydrated preferably with 2-chloro-l,1,2-trifluorotriethylamine in an inert organic solvent such as tetrahydrofuran, methylene chloride, acetonitrile, etc. at room temperature for a prolonged period of time, or with thionyl chloride in pyridine solution, at a temperature below C. and for a short period of time, in the order of to 10 minutes, to produce a mixture of 1,3-dihydrocarbon substituted 20 ethylenedioxy 5,10 methylene-19-nor-A -pregnenes with the corresponding A -isomers. Upon hydrolysis of the latter with p-toluenesulfonic acid in acetone solution, under conventional conditions give rise to a mixture of the corresponding 1,3 disubstituted 5,10 methylene- 19-nor-A -pregnen-20one (III; R =H, acyloxy) and 1,3 disubstituted 5,10 methylene 19 nor A pregnen- 20-one compounds (IV; R =H, acyloxy), which are separated by chromatography on Florisil or neutral alumina.

Alternatively, the dehydration at C-3 and the hydrolysis of the ketal group at C-20 may be accomplished in one step, by reaction of the 1,3-disubstituted 3-hydroxy- ZO-ethylenedioxy compounds (II) with dry hydrogen chloride in acetic acid solution.

The 17a-acyloxy compounds (III and IV; R -=acyloxy) may be saponified with a dilute solution of potassium hydroxide in methanol, at reflux temperature, to the corresponding 17a-hydroxy compounds (IH and 1V; R'- =OH) and reesterified conventionally with acid anhydrides of less than 12 carbon atoms in benzene solution and in the presence of p-toluenesulfonic acid.

Catalytic hydrogenation of III and IV in the presence of a heavy metal catalyst, preferably in the presence of a palladium on charcoal catalyst and using a lower aliphatic alcohol as solvent produces the saturated compounds, by absorption of 1 molar equivalent of hydrogen when R and R are lower alkyl groups or from 2 to 5 molar equivalents when R and/or R are alkenyl or drogenation is preferably conducted at room temperature.

and atmospheric pressure; these conditions are not critical. In another aspect of the present invention, catalytic hydrogenation of the 3-alkyl, alkenyl or alkinyl derivatives of 5,10 seco 5,19 cyclo A -pregnatrien-- 20-one compounds (VI), (Obtained by acid hydrolysisof the corresponding ZO-ethylenedioxy derivatives de scribed in the aforementioned patent application) using essentially the same conditions as hereinbefore described for the LEI-disubstituted derivatives, give rise to the 30:

and 3/3 alkyl 5,10- methylene l9-nor-pregnanes (VII),

predominating the fit-isomer, by absorption of 2 to 4 molar equivalents of hydrogen, depending on the substituent at C-3.

The following examples illustrate the invention but are not intended to limit its scope:

PREPARATION l I II 3-ethinyI-5,ltkseco-SJQ-cyclo- A -pregnatrien-20-one.

3,16a-dimethy1-5,10-seco-5,19-

cyclo-A -pregnatrien-20- one. 3-ethy1-16B-methyl-5,10-seco-5,19- cyclo-A pIegnatrien-ZO- one. 3-ethinyl-16a-methyl-5,10-seco- 5,19-cycl0-A -pregnatrien- 20-one. 3-vinyl-16B-methyl-5,10-seco-5,19- cyclo-A -pregnatrien-20- 3-ethinyl-20-ethylenedioxy-5,10-

seco-5,19'cyc1o-A -pregnatriene.

3,16mlimethyl-20-ethylenedioxy- 5,1O-seco-5,l9-cyclo-A pregnatriene.

3-ethy1-16fl-methyl-20-ethylenedioxy-5,10-seco-5,19-cyclo- A pregnatriene. 3ethiny1-1Sa-methyI-QO-ethylenedioxy-5,l0-seco-5,l9-cyclo- A pregnatriene. 3-vinyl-16fi-methy1-20ethyleuedioxy-5,1U-seco-5,19-cyclo- A 00) -pregnatriene.

The acetate of 3,16a-dimethyl20- ethylenedioxy-5,10-sec0-5,19- clyclo-n -pregnatrien-17a- 0 one.

The acetate 0i 3,16u-dimethyl-5J0- seco-5,19-cyclo-A -preguatrien-17a-o1-20-one.

The acetate of3-viny1-16a-methyl- 5,10-sec0-5,19-cyclo-A 1.4. preg-natr1en-17a-ol-20-one.

The acetate of 3-vinyl-16a-rnethyl- 20-ethylenedioxy-5,10-seco-5,19 cyclo-A -pregnatrien-Ha- The acetate of 3-propy1-20-ethylenedioxy-fi,10-seco-5,19-cyclo- A -pregnatrien-fla-ol.

The acetate of 3-vinyl-20-ethyl- 1enedioxy-5,10-seco-5,19'cyclo- N pregnatrien-ma-ol.

The acetate of 3-propyl-5,10-seco- 5,19-cyclo-A pregnatrien- 17a-ol-20'one.

The acetate of 3-vinyl-5,10-seco- 5,19-cyclo-A -prcgnatrien- 17a-o1-20-one.

'Example I A solution of 2.5 g. of 1u-rnethyl-20-ethy1enedioxy- 5,10-methylene-l9-nor-pregnan-3-one, obtained as described in my copending application Serial No. 346,074, filed February 20, 1964, in cc. of ether was added dropwise, over a 15 minute period, to 25 cc. of 4-N- methylmagnesium bromide solution in ether, under stirring, and the reaction mixture was stirred at room temperature under anhydrous conditions for 4 hours further. After this time it was treated carefully with saturated sodium sulfate solution and solid sodium sulfate, the inorganic material was filtered off and washed well with ether, and the filtrate evaporated to dryness. The residue was crystallized from acetone-hexane, thus affording 1oz,3-. dimethyl 20-ethylenedioxy 5,10-methylene-19-nor-pregnan-3-ol.

Example 11 A solution of 1 g. of 1a,3-dimethyl-20-ethylenedioxy- 5,IO-methylene-19-nor-pregnan-3-ol in 7 cc. of dry pyri-, dine was cooled to 10 C., treated with 0.4 cc. of thionyl I chloride and the mixture allowed to stand for 10 minutes at this temperature. Ice-water was added and the product extracted with methylene chloride. The organic extract was washed with water, hydrochloric acid solution, so-

dium bicarbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue, consisting of a mixture of 1a,3 dimethyl-ZO-ethylenedioxy-S,10-methylene-l9-nor-A -pregnene, dioxy-S,10-methylene-19-ncr-A -pregnene was dissolved and 1a,3-dimethyl-20-ethylene in 60 cc. of acetone and treated with 100 mg. of p-toluenesulfonic acid, and the reaction mixture was kept at room temperature overnight. It was then poured into ice water, extracted with ethyl acetate and the organic extract washed with water to neutral, dried and evaporated to drymess. The residue was chromatographed on 50 g. of neutral alumina, thus producing la,3-dimethyl-5,IO-methylene-l9-11or-A -pregnen-20-one and 1u,3-dimethyl-5,lO- methylene-19-nor-A -pregnen-2O-one in pure form.

Example IV Into a suspension of 1 g. of 1u,3-dimethyl-20-ethylenedioxy-5,10-methylene-19-nor pregnan-3-ol in 35 cc. of glacial acetic acid, there was passed a slow stream of dry hydrochloric acid; after 10 minutes all the solid material was dissolved. The gas was passed through the reaction mixture for a total of 5 hours. The solution was concentrated to about one third its initial volume by distillation under reduced pressure at 35 C., then it was poured into ice-water. The product was extracted with ether, washed Upon treatment of these compounds with hydrogen chloride in acetic acid, in accordance with the method of Example IV there were produced respectively,

1u-ethyl-3-methyl-5,10-methylene-19-nor-A -pregnen-20- one and 1a-ethyl-3-methyl-5,1O-methylene-19-nor-A -pregnen-20- one;

1u-vinyl-3-methyl-5,1O-methylene-19-nor-A -pregnen- 20-one and 1a-vinyl-3-methyl-5,1O-methylene-19-nor-A -pregnen- 20-one and 1a-ethinyl-3-methyl-5,1O-methylene-19-nor-A -pregnen 20-one and 1a-ethinyl-3-methyl-5, IO-methylene-19-nor-A -pregnen- 20-one.

xample VI A solution of 5 g. of 1a,16a-dimethyI-ZO-ethylenedioxy- 5,10-methylene-19-nor-pregnan-3-one in 250 cc. of thiophenefree benzene was treated with 27.5 cc. of 4 N methylmagnesium bromide in ether and the mixture refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness.

Recrystallization from methylene chloride-hexane afforded la,3,16ot trimethyl-ZO-ethylenedioxy-5,10-methylene-19-nor-pregnan-3-ol.

In a similar manner, the compounds mentioned below under I were treated with the indicated Grignard reagent, to produce the compounds listed under II.

I Reagent 1 1a-methy1-20-ethy1ene-dioxy-5,ltl-methylene-lQ-norpregnan 3one.

1a-vinyl-20-ethylenedioxy-5All-methylene-19-nor-pregnan-3-one.

1a-ethy1-20-ethy1enedioxy5,IO-methylene-lQ-nor-pregnan-3 oue.

1m,16a-dimethyl-20ethylenedioxy ii,lll-methyltmfi-lQ- Ethinylmag'nesi m bromide 1a,16a-dimethyl-3ethinyl-20-ethylenedioxy-5,10-

nor-pregnaIi-3-0ne. methylene-1Q-nor-pregnan-B-ol.

la-ethinyl-l6a-methyl-20ethylenedi0Xy-5,10-methyl- Methylmagnesmm bromide lwethinyl-il,16a-dimethyl-20-ethyIenedj xy-5,10- v ene-l9-nor-pregnan-3one. v methylene-19nor-pregnan-3bl. Y

la-ethyl-lfifl-methyl-20ethylenedioxy-5JU-methylene- Propylmagnesmm bromide 1a-ethyl-3-p1()pyl-16fi-methy1-20-ethylenedj .5 lo.

19-nor-pregnan-3-one. methylene-19-nor-pregnan-3o1.

la-vinyl-lGB-methyi-Zflethylenedioxy-5,10-methylene- Vmylmagnesmm bromide 10:,3 d1V1l1Y1-1Gfl-methyl-Zflethylenedioxy-il0. 11 w 19-nor-pregnan-3ene. ylene-lQmor-pregnan- -ol. 7

The acetate of1u,16a-dimethyl-20ethylenedioxy-5,10- Ethmylmagneslum bromide The acetate of 111,1fiwdimethyLS-ethinyI-ZO-ethylmethylene-19-nor-pregnan-17a-ol-3pne.

Propylmagnesium bromide Vinylmagnesium bromide 1a-Ineth371-3-Viny1-20ethylenedioxy-5,ltl-methylenel9-nor-pregnan-3-ol.

nor -pregnan-3-o 1a-ethyLK-propyl-idethylenedioxy-5,IU-methylene- 19-nor-pregnam -01.

The acetate of 1a-vinyl-lfia-methyl-wethylenedioxy- Methylmagnesium bromide The acetate of la-vinyl-S,lfiwdimethyl-20-ethylene- 5,IO-niethylene-l9-nor-pregnan-17a-ol-3-one. d1oxy-5,10 methy1ene-19nor-pregnane-3,17a-di01. The acetate of1a-p1-opy1-20ethyle11edioxy-5,lfl-meth- Propylmagneslum bromide The acetate Of1a,3-dipr0pyl-20etl1ylenedioxy-5,1(I-

ylene-lQ-norpregnau-17a-ol-3-o11e. The acetate of 1a-vinyl-20-ethylened1oxy'5,Ill-methylene-l -nor-pregnan-l7a-ol-3-one.

methylene-19-nor-pregnane-3,17a-diol.

Ethylmagnesium bromide The acetate of 1a-vinyl-3ethyl-20ethylenedioxy-5,

10-methylene-19-nor-pregnane-3,l7a-diol.

The acetate of 1a-propinyl-20-ethylenedioXy-5,1D-meth- Methylmagnesium bromide The acetate of la-propinyLB-methylQO-ethylenediylene-l9-nor-pregnan17a-o1-3-one. The acetate of 1a,16a-dimethyl-ZOethyleuedroxy-S,10-

methylene-l9-nor-pregnan-17aoI-3-one.

Methylmag'nesiurn bromide The acetate of 101,3,1fia-trimethy1-20ethylenedioxyto neutral, dried and evaporated to dryness. Chromatography of the residue on 50 g. of Florisil afforded 10,3-dimethyl-5,IO-methylene-l9-nor-A -pregnen-20-one and 1a, 3-dirnethyl-5,1O methylene-19-nor-A -pregnen-2O-one in pure form, identical to the products obtained by the method of Example II.

Example V Example VII By following the method of Example III, the compounds obtained in the preceding example were dehydrated with 2-chloro-1,1,2-trifluorotriethylamine, hydro lized with p-toluenesulfonic acid in acetone and chromatographed on Florisil, to produce, respectively: 1a,3,16a-trimethyl-5,1O-methylene-l9-r1or-A -pregnen- 20-one and 111,3,16a-trimethyl-5,10-methylene-19- nor-A -pregnen-20-one;

1a-methyl-3 -vinyl-5, 1 O-methylene-19-nor-A -pregnen- 20-one and 1a-methyl-3-vinyl-5,10-methylene-19- nor-A -pregnen-2O-one;

, 1a-vinyl3 -ethyl-5,1O-methylene-19-nor-A fipregnen- 20-one and 1u-vinyl-3-ethyl-5,10-methylene-l9-nor- A -pregnen-2O-one;

1u-ethyl-3-propyl-5,1O-methylene-l9-nor-A -pregnen- 20-one and 1a-ethyl-3-propyl-5,10-methylene-19- nor-A -pregnen-20-0ne;

7 1a,l6a-dimethyl-3-ethinyl-5,l0methylene-l9-nor-A pregnen-ZO-one and la,16e-dimethyl-3-ethinyl-5,l0- methylene-19-nor-A -pregncn-2O-one;

Ia-ethinyl-B, l 6a-dimethyl-5 l-methylene-l9-nor-A pregnen-ZO-one and 1a-ethinyl-3,16a-dimethyl-5,10- methylene-19-nor-A -pregnen-2O-one;

1a-ethy1-3-propyl-l6fi-methyl-5,l0-methylene-19-nor- A -pregnen-20-one and 1a-ethyl-3-propyl-16/8-methyl-. l O-methylene-19-nor-A -pregnen-20-one 1a,3-divinyl-l6f3-methyl-5,10-methylene-l9-nor-A pregnen-ZO-one and la,3-divinyl-16fi-methyl-5,l0- methylene-19-nor-A -pre-gnen-20-one;

the acetate of 1a,16u-dimethyl-3-ethinyl-5,IO-methylene-l9-n0r-A -pregnen-17a-ol-20-one and the acetate of 1a,16u-dimethyl-3-ethinyl-5,10-methylene-19-nor- A -pregnen-17a-ol-20-one;

the acetate of 1a-vinyl-3,l6u-dimethyl-5,IO-methylene- 19-nor-A -pregnen-17a-ol-20-one and the acetate of 1m-vinyl3,16a-dimethyl-5,l0-methylene-l9-nor- A -pregnen-17a-ol-20-one;

the acetate of 1a,3-di-propy1-5,l0-methylenc-l9-nor-A pregnen-l7a-ol-20-one and the acetate of la,3-dipropyl-S,IO-methylene l9-nor-A -pregnen-17a-ol-20- one;

the acetate of 1a-vinyl-3-ethyl-5,l0-methylene-19-nor- A -pregnen-17m-ol-20-0ne and the acetate of lot-vinyl- 3-ethyl-5,IO-methylene-19-nor-A -pregnen-l7a-ol- 20-one;

the acetate of 1a-propinyl-3-methyl-5,IO-methylenel9-nor-A -pregnen-17a-ol-20-one and the acetate of la-propinyl-3-methyl-5,l0-methylene-l9-nor-A pregnen-17a-ol-20-one;

the acetate of 1a,3,16a-trimethyl-5,IO-methylene-l9- nor-A -pregnen-17a-ol-20-one and the acetate of 111,3,16a-trimethyl-5,1O-methylene-19-nor-A -pregnen-l7a-ol-20-one.

Example VIII A solution of 1 g. of la,3dimcthyl-5,IO-methylene 19-n0r-A -pregnen-2O-0ne in 100 cc. of methanol was hydrogenated in the presence of 100 mg. of previously reduced 5% palladium charcoal catalyst, until the absorption of hydrogen ceased (1 molar equivalent). The catalyst was filtered off and the filtrate evaporated to dryness. Crystallization of the residue from acetoneether :gave the pure la,3fl-dimethyl-5,10-methylene-19- nor-pregnan-ZO-one.

The same product was obtained when 1u,3-dimethyl- 5,1O-methylene-19-n0r-A -pregnen-20-one was used as starting material.

Example IX In accordance with the hydrogenation method described in the preceding example, 10:,3,l6a-trimethyl-5,10methylcne-l9-nor-A -pregnen- -one, la-ethyI-B-methyI-S,10-methylene-19-nor-A -pregnen- 20-one, 1a-ethyl-3-propyl-l6fi-methyl-5,10-methylene-l9-nor- A -pregnen-20-one, and the acetate of lu,3-dipropyl-5,10-methylene-19- nor-A -pregnen-17a-ol-20-one were converted into the corresponding saturated derivatives, namely 101,3 9,1Gm-trimethyI-S,1O-methylene-19-n-or-pregnan- 20-one, 1a-ethyl-3B-methyl-5,10-methylene-19-nor-pregnan 20-one, 1a-ethyl-3B-propyl-16fl-methyl-5,lO-methylene-l9-norpregnan-ZO-one and the acetate of 1a,3fl-dipropyl-5,IO-methylene-19-nor-pregnan-17aol-20-one.

I II

methyl-3B4 6a-dimethy15,10-

la-ethinyl-ll,16a dimethy1-5,10-

methylene-l9-nor-pregnan-20- methylened -nor-A -pregnen- 20-one.

1a,3-divinyl-16B-methyl-5,10-

methylenc-19-nor-A -pregnen- 20-one.

the acetate of 10:, lfia-dimethyl-S- ethinyl-5,lO-methylene-lQ-nor- A -pregnen-17a-ol-20-one.

the acetate of 1a-propinyl-3- methyl-5,IO-methyIene-lQ-nor- A -pregnen-17a-ol-20one.

one. 1a,35 diethyl-16B-methyl5,10-

methy1ene-19-nor-pregnan-20- one.

the acetate oi1a,l6a-dimethy1- 3fl-ethyl-5,IO-methylene-lQ-norpregnan-17a-ol-20-one.

the acetate of 1a-pr0pyl-3B- methyl-5,10-methylene-19-nor- PIQgHEtII-I'Iafll-QU-OIIB.

Example XI In the method of the preceding example there was used 1a-vinyl-3-rnethyl-5,10-methylene-19 nor A -pregnen-20-one as starting material and the uptake of hydrogen was of 2 molar equivalents, thus producing 1ozethyl-3-fi-metl1yl-5,10-methylene-19-nor-pregnan 20-one, identical to the obtained in Examples IX and X.

Example XII A solution of 1 g. of the acetate of 1a,3,16a-trimethyl- 5,l0-methylene 19 nor-A -pregnen-l7a-ol-20-one in 50 cc. of methanol was refluxed for 3 hours with 500 mg. of potassium hydroxide dissolved in 1 cc. of water; it was then poured into ice water, the precipitate collected, washed with water to neutral and dried, thus producing a crude compound which upon recrystallization from methylene-chloride-ether afforded 111,3,160; trimethyl 5,10- methylene-19-nor-A -pregnen-17u-ol-20-one.

By the same method, the acetate of 1a,16a-dirnethyl-3-ethinyl-5,10-methylene-19-nor-A prcgnen-17a-ol-20-one,

the acetate of 1a-viny1-3,16a-dimethyl-5,10-methylene-19- nor-A -pregnen-l7a-ol-20-one.

the acetate of 1a,3-dipropyl-5,10-methy1ene-19-nor-A pregnen-17a-ol-20-onc,

the acetate of 1a-propinyl-3-methy1-5,IO-methylene- 19-nor-A -pregnen-17a-ol-20-one,

the acetate of 1a,16a-dimethy1-3fl ethy1-5JO-methylene- 19-nor-pregnan-l7a-ol-20-one and the acetate of la-propyl-3 8-methyl-5,IO-methylene- 19-nor-pregnan-17a-ol-20-one were converted into the corresponding free compounds.

Example XIII To a solution of 500 mg. of 1u,16a-dimethyl-3;3-ethyl-- 5,10-methylenel9-nor-pregnan-17a-ol-20-one in 10 cc. of anhydrous benzene there were added mg. of p-toluene sulfonic acid and 1.5 cc. of caproic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mix-1 ture stirred to effect hydrolysis of the excess anhydride. The benzene layer Was separated and washed with 10%" Drying, evapora sodium carbonate solution and water. tion and crystallization of the residue from ether-hexane produced the caproate of 111,16u-dimethy1-3f3-ethyl-5J0-' methylene-19-nor-pregnan-17a-o1-20 one.

By the same method,

were esterified with propionic, caproic and cyclopentyl propionic anhydrides to produce the respective propionates, caproates and cyclopentylpropionates.

Example XIV A solution of 1 g. of 3-methyl-5,10-seco-5,l9 cyclo- A -pregnat1ien-20-one in 50 cc. of ethanol was added to a suspension of 250 mg. of a palladium on charcoal catalyst, previously reduced. The mixture was hydrogenated at room temperature, at atmospheric pressure, until the absorption of hydrogen ceased (approximately 2 molar equivalents of hydrogen were absorbed). The catalyst was removed by filtration, and the solvent evaporated under reduced pressure, water was added to the residue and the product was extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Crystallization from acetone-hexane afiorded 3B-methyl-5,lO-methylene-l9-nor-pregnan-20-one.

By the same method, the compounds mentioned below under I were converted into the saturated compounds listed under 11: Y

I II

3,6,l6a-dimethyl-5,IO-methylene- 19'nor-pregnan-20-one.

The acetate of3B,16t-dimethyl- 5,IO-methylene-19-nor-pregnan- 17a-0l-20-one.

The acetate of 3B-propyl-5,10-

methylene-1 -nor-pregnan-lmol--one.

lo.Al (w) .2- regnatrien-20- one. Sethyl-l6B-rnethyl5,l0seco-5,19 cycle-A -pregnatrien-20- one.

The acetate of 3,16wdimethyl-5J0- seco-5,19-cycl0-A pregnat1'i81117a-01-20-0I1B.

The acetate of 3-propyl-5,10-seco- 5,19-cycloA -pregnatrien- I'IaOPZO-OIIB.

Example XV Example XV was repeated but using 3-Vi-nyl-16'fi-methyl-5,10-seco-5,l9-cyclo-A -pregnatrien-20 one, and the uptake of hydrogen was of 3 molar equivalents only. There was thus obtained 3,6-ethyl-l6fi-methyl5,10-methylene-l9-nor-pregnan-20-one, identical to that obtained in Example XIV.

Similarly, the acetate of 3-vi-nyl-5,10-seco-5,l9=cyclo- A -pregnatrien-l7a-ol-20-one and the acetate of 3- viny-l-l6a-methyl-5,l0-seco-5,l9- cyclo A -pregnatrien-17a-ol-20-one were converted respectively into the acetate of 3 fl-ethyl-S ,10-methylene-19'-nor-pregnan-17a-o1- 20-one and the acetate of 3B-ethyl-l6a-methyl5,lO-methylene-l9-nor-preg:uan-l7a-ol-20-one.

' Example XVII In accordance with the method of Example XII, the acetate of 3 fl-propyl-S, 10 methylene-19-nor-pregnan- 17 x-0l- 20-one, the acetate of 35,16a-dimethyl-5,l0-methylene-l9- nor-pregnan-17a-ol-20 one and the acetate of Sfi-ethyl-l6a-methyl-5,10-methylene-l9- nor-pregnan-17u-ol-20-one were converted into the corresponding free compounds, namely, 3 fl-propyl-5,10-methylene-l9-nor-pregnan-l7ot-ol- 20-one,

3 ,8, 1 6ot-dif1'16ihYl-5, 1 O-methylene-19-nor-pregnan-17aol-20-one and 3 8-ethyl-16u-methyl-5 ,10-methylene-19-norpregnau-lh-ol-ZO-one.

Upon reesterification of these t-hydl'OXY compounds with p-ropionic, caproic and undecenoic anhydrides, in accordance with the method of Example XIII, there were produced the corresponding propionates, caproates and undecenoates.

I claim:

1. A compound of the following formula:

mg W wherein R and R are selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl; R is selected from the group consisting of hydrogen, hydroxy and an acyloxy group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen, a-methyl and B-methyl.

2. 111,3 dimethyl 5,10 methylene 19 nor A pregnen-ZO-one.

3. loc,3,160c trimethyl 5,10 methylene 19 nor- A -pregnen-20-one.

4. 1oz ethyl 3 methyl 5,10 methylene 19 nor- A -pregnen-20-one.

5. 1a,l6m dimethyl 3 ethinyl 5,10 methylene- 19-nor-A -pregnen-17a-ol-20-one.

6. The acetate of 1 t-vinyl-3-ethyl-5,l0-methylene-19- nor-A -pregnen-17oz-0l.

7. A compound of the following formula:

wherein R and R are selected from the group consisting of lower alkyl, lower alkenyl and lower alkinyl; R is selected from the group consisting of hydrogen, hydroxy and an acyloxy group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen, amethyl and [i-methyl.

8. loc,3 dimethyl 5,10 methylene 19 nor A pregnen-ZO-one.

11 12 9. 1u,3,16u trirnethyl 5,10 methylene 19 norwherein R is selected from the group consisting of hy- A -pregnen-2O-one. drogen, hydroxy and an acyloxy group of less than 12 10. 1oz vinyl 3 methyl 5,10 methylene 19- carbon atoms; R is selected from the group consisting nor-A -pregnen-20-one. of hydrogen, a-methyl and fi-methyl; R represents a lower 11. The acetate of 1a-vinyl-3-ethyl-5,10-methylene-19- 5 alkyl radical and R represents a lower ,alkyl group. nor-A -pregnen-l7a-ol-20-one. 14; 111,35 dimethyl 5,10 methylene 19 nor- 12. 1oz,3,16a trimethyl 5,10 methylene 19 norpregnan-ZO-one. A -pregnen-17u-o1-20-one. 15. 1a ethyl 3,8 methyl 5,10 methylene- 19-,

13. A compound of the following formula: nor-pregnan-ZO-one.

CH3 16., The acetate of 1a,16u-dimethyl-3B-ethyl-5,IO-methylene-19-nor-pregnan-17a-ol-20-one. 21 References Cited by the Examiner UNITED STATES PATENTS 15 3,185,714 5/1965 Knox 260397.3

LEWIS GOTTS, Primary Examiner. H. A. FRENCH, Assistant Examiner. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 